The sympathetic nervous system and angiotensin II (ANG) are implicated in obesity-induced hypertension (HT), but the mechanisms are poorly defined. Our preliminary data support a role for brain ANG signaling in increased arterial pressure (AP) in diet-induced obese (DIO) mice. Additional data reveal striking endoplasmic reticulum (ER) stress in key brain cardiovascular control regions (SFO-PVN axis) in DIO and indicate that chemical manipulation of ER stress influences sympathetic nerve activity (SNA) and AP in this model. Our data also demonstrate that DIO causes oxidative stress in the SFO-PVN axis and this is linked to ER stress. Furthermore, new preliminary data show that both ER stress and oxidative stress in this brain axis are coupled to leptin signaling in DIO mice. Additional new data raise the possibility that DIO-mediated oxidative and ER stress in the brain modulate the facilitatory effect of brain ANG on energy expenditure (EE). Based on these promising, multifaceted preliminary data, we will address four innovative and interrelated concepts: 1) dissociation between central mechanisms controlling energy homeostasis and cardiovascular responses in obesity-HT;2) brain ER stress, a new disease paradigm, as a key underlying mechanism;3) the role of redox signaling, with potential links to ER stress pathways, in obesity-HT and 4) the SFO-PVN axis as a major player in DIO-mediated cardiovascular and metabolic dysregulation. We will address the overall hypothesis that in DIO mice, increased brain ANG and/or leptin signaling promotes ER stress and oxidant stress in the SFO-PVN axis. We postulate that this ER/oxidant stress contributes to the increased renal SNA and AP in DIO mice, but conversely acts in the SFO-PVN axis to blunt or reverse brain ANG- and/or leptin-mediated facilitatory effects on thermogenic SNA and EE in this model of obesity-HTN. To address this innovative hypothesis, we have assembled multiple sophisticated research tools, including 1) genetically engineered mouse models and viral vectors that allow brain site-selective targeting of key ANG, oxidant and ER stress molecules;2) state-of-the-art assays for visualizing and quantifying ER stress;3) sophisticated integrative physiology for evaluating AP, SNA and EE. A notable strength ofthe project is the extensive interfacing, both conceptual and technical, with Projects 2 and 3.
Obesity-induced HT is a major global health problem that involves the sympathetic nervous system. This research has the potential to advance understanding of fundamental molecular and physiologic mechanisms by which the brain triggers sympathetic activation and HT in obesity, and could have implications for novel therapies targeting the neurogenic component of obesity-induced HT and its cardiovascular complications.
|Yoon, Young-Sil; Tsai, Wen-Wei; Van de Velde, Sam et al. (2018) cAMP-inducible coactivator CRTC3 attenuates brown adipose tissue thermogenesis. Proc Natl Acad Sci U S A 115:E5289-E5297|
|Imai, Yumi; Fink, Brian D; Promes, Joseph A et al. (2018) Effect of a mitochondrial-targeted coenzyme Q analog on pancreatic ?-cell function and energetics in high fat fed obese mice. Pharmacol Res Perspect 6:e00393|
|Morselli, Lisa L; Claflin, Kristin E; Cui, Huxing et al. (2018) Control of Energy Expenditure by AgRP Neurons of the Arcuate Nucleus: Neurocircuitry, Signaling Pathways, and Angiotensin. Curr Hypertens Rep 20:25|
|Nair, Anand R; Agbor, Larry N; Mukohda, Masashi et al. (2018) Interference With Endothelial PPAR (Peroxisome Proliferator-Activated Receptor)-? Causes Accelerated Cerebral Vascular Dysfunction in Response to Endogenous Renin-Angiotensin System Activation. Hypertension 72:1227-1235|
|Seoane-Collazo, Patricia; Roa, Juan; Rial-Pensado, Eva et al. (2018) SF1-Specific AMPK?1 Deletion Protects Against Diet-Induced Obesity. Diabetes 67:2213-2226|
|Schmidt, Eric A; Despas, Fabien; Pavy-Le Traon, Anne et al. (2018) Intracranial Pressure Is a Determinant of Sympathetic Activity. Front Physiol 9:11|
|Scroggins, Sabrina M; Santillan, Donna A; Lund, Jenna M et al. (2018) Elevated vasopressin in pregnant mice induces T-helper subset alterations consistent with human preeclampsia. Clin Sci (Lond) 132:419-436|
|Forrester, Steven J; Booz, George W; Sigmund, Curt D et al. (2018) Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 98:1627-1738|
|Sandgren, Jeremy A; Linggonegoro, Danny W; Zhang, Shao Yang et al. (2018) Angiotensin AT1A receptors expressed in vasopressin-producing cells of the supraoptic nucleus contribute to osmotic control of vasopressin. Am J Physiol Regul Integr Comp Physiol 314:R770-R780|
|Pellegrinelli, Vanessa; Peirce, Vivian J; Howard, Laura et al. (2018) Adipocyte-secreted BMP8b mediates adrenergic-induced remodeling of the neuro-vascular network in adipose tissue. Nat Commun 9:4974|
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